Download Drugs and Inadequate Lactation

Medicines Q&As
UKMi Q&A 73.3
Drug treatment of inadequate lactation
Prepared by UK Medicines Information (UKMi) pharmacists for NHS healthcare professionals
Date prepared: 20 April 2010
Background
Lactation is the physiological completion of the reproductive cycle. It is a complex process involving
physical and emotional factors and the interaction of multiple hormones, the most important of which is
prolactin. Oxytocin is involved in the milk ejection reflex (1,2,3).
An intact hypothalamic-pituitary axis regulating prolactin and oxytocin levels is essential for the
initiation and maintenance of lactation. Successful lactation requires both milk synthesis and milk
release into the alveoli and lactiferous ducts. When milk is not removed, the increased pressure
lessens capillary blood flow and inhibits the lactation process. Lack of suckling reduces prolactin
release from the pituitary gland. Sensory nerve endings, located mainly in the areola and nipple, are
stimulated by suckling. Stimulation of afferent neural reflex pathways via the spinal cord and
hypothalamus, produce secretion of prolactin and oxytocin (3). The release and production of prolactin
is dependent on the inhibition of prolactin inhibitor factor, which is produced by the hypothalamus and
dopamine-releasing neurones (3,4).
As lactation progresses, the prolactin response to suckling diminishes and milk removal becomes the
driving force behind milk production (5). This is now known to be due to the presence in secreted milk
of a whey protein that is able to inhibit the synthesis of milk constituents (6,7).
The definitive indicator of an adequate milk supply is infant weight gain in the early neonatal period (8).
The evidence (9) suggests that when babies are breastfeeding well:
 Maximum weight loss occurs by 72 hours: “Day 3”.
 Maximum loss of bodyweight is 6-8%
 Birth weight is regained by 5-7 days of life
Other indicators are:
Frequent wet (heavy) nappies, with pale, odourless urine from 48-72 hours onwards and a change in
stool colour from “black” meconium at 0-24 hours to yellow at 72-96 hours.
Poor weight gain, static weight, or weight loss, at any time after the first week, is a cue for the health
professional caring for the mother to take an active interest. In the early days sufficient milk is usually
being produced, but it may not be reaching the baby efficiently.
Causes of inadequate lactation
Since lactation is such a complex process, it is unsurprising that there are a number of causes of
insufficient milk supply. A review discussed risk factors for failed lactogenesis (10). While insufficient
milk supply is a commonly perceived problem by mothers it actually occurs rarely (8). The most
common causes of prolactin deficiency include postpartum pituitary necrosis (Sheehan syndrome) and
other causes of anterior pituitary dysfunction. Other causes of prolactin deficiency are medications
(such as dopamine, ergot preparations and pyridoxine). Nicotine also affects prolactin release in
response to a sucking stimulus and smoking mothers may have decreased milk yield (11). Other
factors include bulimia, retained placental fragments (11), breast surgery (12), obesity (13,14,15) and
postpartum haemorrhage (8). Prolonged stress may impair the milk ejection reflex by reducing the
release of oxytocin during a feed (16).
Because an apparently low milk supply is one of the most common reasons for discontinuing
breastfeeding (17), both mothers and clinicians have sought means to address this problem.
From the National Electronic Library for Medicines. www.nelm.nhs.uk
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Medicines Q&As
Answer
Use of drugs to initiate or augment milk supply
Galactagogues (drugs for faltering milk supply) should only be used after thorough evaluation for
treatable causes such as poor attachment, and when increased frequency of breastfeeding, pumping
or hand expression of milk has not been successful (18).
Indications for the use of galactagogues are (1):
 Increase of a faltering milk supply due to maternal or infant illness and prematurity
 Separation of mother and infant
 After a period of milk expression by hand or with a pump when a decline in milk production
may occur after several weeks
 Adoptive nursing
 Relactation (re-establishing milk supply after weaning)
Specific galactagogues
There are no products in the U.K that are licensed for use as galactagogues. Such use is “off-label”.
Domperidone (Prescription Only Medicine (POM), but available as Pharmacy medicine (P) if used for
relief of postprandial symptoms)
Over-the-counter (OTC) availability may mean that mothers can self-medicate which is undesirable. A
health professional should always be involved in the decision to use a galactagogue.
Domperidone is a dopamine antagonist. Unlike metoclopramide, it passes poorly into the brain and
has few central nervous system (CNS) side effects (8). It produces significant increases in prolactin
levels and has proved useful in enhancing lactation (19,20,21) including use in mothers of preterm
infants (22).
The regimen most commonly used is 10-20mg, orally, three to four times daily (8). Further studies are
needed to define the optimal regimen and length of treatment (23).
Concentrations of domperidone in milk vary according to the maternal dose. Following a dose of 10mg
three times daily, reported average milk concentrations ranged from 1.2 micrograms/L (23) to 2.6
micrograms/L (8). Because of extensive first pass and gut-wall metabolism, oral bioavailability is only
13-17% (24). The total amount of drug ingested by the infant via milk is very small (about 180
nanograms/kg/day) (23). The mean relative infant dose was 0.01% after a 30 mg daily dose and
0.009% at 60 mg (25).
The U.S. FDA issued a warning in June 2004 about the use of domperidone in inadequate lactation
due to concerns over cardiac problems following intravenous use (26). Domperidone can prolong the
QT interval. As discussed above, amounts of the drug in milk are very low and lactation experts do not
consider the warnings relevant to its use in inadequate lactation (27,28). However, the possible
cardiac risk should be borne in mind in “at risk” mothers e.g. those on potent CYP34A inhibitors such
as ketoconazole and erythromycin (18).
In one study in 46 mothers who delivered infants of less than 31 weeks gestation, domperidone or
placebo was given for lactation failure . The effect of domperidone on macronutrient composition of
breast milk was also studied (29). By day 14, breast milk volumes increased by 267% in the treatment
group compared to 18.5% in the placebo group. Mean breast protein declined by 9.6% in the
domperidone group but increased by 3.6% in the placebo group. Changes in energy, fat,
carbohydrate, sodium and phosphate content did not differ significantly between the groups. Increases
in breast milk carbohydrate (2.7& vs –2.7%) and calcium ( 61.8% vs –4.4%) were noted in the
treatment group in comparison with the placebo group. No adverse effects were reported in the
mothers or their infants. The authors concluded that domperidone was effective in increasing milk
volume of mothers of preterm infants without substantially altering nutrient content. The full
significance of the increase of calcium concentration is unclear and requires further study.
Metoclopramide (POM)
From the National Electronic Library for Medicines. www.nelm.nhs.uk
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Medicines Q&As
Like domperidone, metoclopramide increases prolactin levels via blockade of dopamine receptors.
Reports of its successful use as a galactagogue have appeared since the 1980s and it is the agent for
which most data have been published (30-34). Metoclopramide has been used in mothers of preterm
infants (31,33) and in the intended mother of a surrogate pregnancy (35).
The increase in serum prolactin and milk production appears to be dose-related with daily doses of 30
and 45mg proving effective and 15mg daily ineffective (30). Although metoclopramide does increase
milk supply, the effect is very dose-dependent and some mothers do not respond (8). Side effects
such as gastric cramping and diarrhoea may limit compliance (8). If no effect is seen within 7 days, it is
unlikely that longer therapy will be effective (8). After discontinuation of medication, the milk supply
may diminish rapidly and a slow tapering of the dose over several weeks (e.g. by 10mg per week) is
recommended in those women who respond (8). Metoclopramide is not suitable for women with a prior
history of depression, and use for more than four weeks is not recommended as this may increase the
risk of depression (8).
Estimated intake of the drug via milk varies from 1 to 24 micrograms/kg/day. These levels are very low
compared to those used to treat reflux in paediatric patients, 100-500 micrograms/kg/day (8).
In one study, the plasma prolactin concentration in 4 of 7 neonates sampled during administration of
metoclopramide to the mother were higher than the highest plasma prolactin level in infants of the
same age with untreated mothers (34).
Sulpiride (POM)
Sulpiride is a selective dopamine antagonist. Limited data suggest successful use as a galactagogue
(36,37). The suggested dose to improve milk supply is 10-20mg, orally, three to four times a day (8),
although use of higher doses of 50mg twice or three times a day has been reported (36,37). Although
significant increases in prolactin are seen, these do not always correlate with increases in milk
production (36,37). No effects on breastfed infants were noted in these studies. Reported
concentrations in breast milk range from 0.26-1.97 mg/L (8). The estimated infant intake of sulpiride
via breast milk has been calculated as 290 micrograms/kg/day (38).
Herbal medications
Various herbal remedies, including milk thistle and fenugreek, have been suggested to improve poor
milk supply. However, there is insufficient evidence of safety or efficacy to recommend such use
(39,40). There may be concerns over the relative potency and quality control of herbal products (8).
Other
In one small study, 19 puerperal women with inadequate lactation (less than 50% normal milk yield)
were randomised to receive thyrotrophin-releasing hormone (TRH) 1mg (n=10) or placebo (n=9) four
times daily by nasal spray for 10 days, starting on day 6 postpartum. Milk yield increased significantly
in the active treatment group whilst there was no significant change in the controls. A further rise in
prolactin and milk yield was seen in seven of the TRH treated group given a second 10-day course at
their own request. No significant changes in levels of TRH, thyroxine or tri-iodothyronine were seen in
either group (41).
A single session of acupuncture had variable effect in 90% of 30 women with postpartum inadequate
lactation (42). Improved lactation was more marked after 3-5 sessions, especially in primiparae within
10 days of delivery. Acupuncture was less effective the longer the duration of inadequate lactation.
Summary

A health professional should always be involved in the decision to use a galactagogue.

Drugs to manage inadequate lactation should only be used where there is objective evidence
to support diagnosis and where non-drug methods have failed.

There are no drugs licensed in the UK to improve lactation.

Domperidone is considered to be the agent of choice for inadequate lactation because of its
superior side effect profile, efficacy, and minimal passage into breast milk.
From the National Electronic Library for Medicines. www.nelm.nhs.uk
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Medicines Q&As

The most commonly used regimen for domperidone is 10-20mg, orally, 3-4 times daily.

Further studies are needed to determine the optimum regimen and duration of treatment.

There are insufficient data to support the use of herbal remedies.
Limitations:
Published reports of drug use in lactation are generally limited to small numbers of subjects or to single
case reports. Quantitative reports are often limited to single time point estimations. Many of the studies
were performed before the introduction of modern lactation management. Few studies have provided
encouragement and instruction to mothers. There are often inconsistencies in inclusion criteria that
could minimise possible differences between drug and placebo groups (18).
References
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Medicines Q&As
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37. Ylikorkala O, Kauppila A, Kivinen S et al. Treatment of inadequate lactation with oral sulpiride and buccal
oxytocin. Obstet Gynecol 1984;63:57-60
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Med 2006;26:29-30
From the National Electronic Library for Medicines. www.nelm.nhs.uk
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Medicines Q&As
Quality Assurance
Prepared by
Elena Grant, West Midlands Medicines Information Service
Contact: [email protected]
Date prepared
10 April 2006 (version 1)
20 April 2010 (partial revision version 3)
Checked by
Jim Glare, West Midlands Medicines Information Service (version 1)
Peter Golightly, Trent & West Midlands Medicines Information Service (partial revision version 3)
Date of check
13 April 2006 (version 1)
30 April 2010 (partial revision version 3)
Search strategy
 Medline search 1951 – date 13/04/2010
1.
LACTATION – DISORDERS.DE. with DT
2.
LACTATION W..DE
3.
(1 OR 2) and human = yes
4.
domperidone.w..de.
5.
3 AND 4
6.
METOCLOPRAMIDE.W..DE.
7.
3 AND 6
8.
SULPIRIDE.W..DE.
9.
2 AND 8

Embase search 1974 – 13/04/2010
1.
LACTATION-DISORDER.DE.
2.
LACTATION.W..DE.
3.
(1 OR 2) AND HUMAN = YES
4.
DOMPERIDONE.W..DE.
5.
3 AND 4
6.
METOCLOPRAMIDE.W..DE
7.
3 AND 6
8.
SULPIRIDE.W..DE.
9.
3 AND 8



Cochrane Library
General Internet search per Google – lactation disorders/inadequate lactation
Natural Medicines Comprehensive Database accessed 18/08/2005, 04/01/2006 and
13/04/2010
In house resources (past enquiries, database)
Clinical experts : Sally Inch, Infant feeding Specialist, Human Milk Bank and Baby Friendly Coordinator, Womens’ Centre, Oxford Radcliffe Hospitals NHS Trust, Peter Golightly, Director,
Trent Medicines Information Service


From the National Electronic Library for Medicines. www.nelm.nhs.uk
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